Oxytocin Induces Retrograde Metaplasticity to Attenuate CocainePreference Behavior

项目总结/摘要 越来越多的研究表明，催产素（OXT）对可卡因有减毒作用 啮齿类动物的奖励行为，因此可以作为可卡因奖励的潜在调节剂进行研究 流程.尽管如此，OXT对可卡因发挥这种调节作用的具体机制- 相关行为尚不清楚。目前的研究项目提出，OXT减弱可卡因- 通过腹侧被盖区多巴胺（DA）神经元的双重机制的相关偏好 （VTA）。最近的证据表明，腹侧被盖区DA神经元上的OXT受体（OXTRs）既增加了多巴胺神经元的紧张性放电， DA神经元和减少兴奋性输入，可能影响DA神经元的阶段性激活。这种减少 在兴奋性输入中，OXT与突触前CB1受体的相互作用是介导的 （CB1Rs）的神经末梢。本项目调查的功能相关性，这一影响使用一本小说 转基因大鼠和病毒递送的shRNA的组合沉默VTA DA OXTRs或突触前 多巴胺能CB1Rs。首先，将在雄性和雌性大鼠中使用免疫抑制剂沉默DA VTA神经元上的OXTRs。 转基因Cre大鼠和OXTRs的Cre依赖性敲低，以确定OXT介导的DA放电的作用 率在行为上，OXT减弱可卡因偏好行为，并且预期OXTRs的沉默对可卡因依赖性的增加是有作用的。 腹侧被盖区DA神经元会减弱这种效应。第二，进一步阐明 OXT通过VTA DA神经元减弱可卡因偏好，VTA多巴胺能输入的CB1受体将被沉默 使用转基因Cre大鼠和在不存在Cre表达的情况下CB1R的shRNA沉默的组合。OXT 已知通过产生内源性大麻素（eCB）来减少神经元兴奋， 通过CB1受体的突触前输入。通过这一点，将评估多巴胺能CB1R沉默的作用， OXT介导的VTA DA相神经元放电。从行为上看，这表明OXT介导的 VTA DA相位放电是OXT介导的可卡因相关偏好衰减的基础。总的来说，这个项目 将利用一种新的工具组合来研究特定的神经机制， 减弱可卡因的奖励，并提供深入了解使用OXT作为可卡因相关的治疗靶点 男性和女性的疾病。

PROJECT SUMMARY/ABSTRACT A growing number of studies have demonstrated that oxytocin (OXT) provides an attenuating effect on cocaine reward behaviors in rodents and therefore may be investigated as a potential modulator of cocaine reward processes. Despite this, the specific mechanism through which OXT exerts this modulatory effect on cocaine- related behaviors remains unclear. The present research project proposes that OXT attenuates cocaine- associated preference via a two-fold mechanism on dopamine (DA) neurons within the ventral tegmental area (VTA). Recent evidence suggests that OXT receptors (OXTRs) on VTA DA neurons both increase tonic firing of the DA neuron and decreases excitatory inputs, likely affecting phasic activation of the DA neuron. This decrease in excitatory inputs has been shown to be mediated by an OXT interaction with presynaptic CB1 receptors (CB1Rs) on glutamatergic terminals. This project investigates the functional relevance of this effect using a novel combination of transgenic rat and virally-delivered shRNA to silence VTA DA OXTRs or presynaptic glutamatergic CB1Rs. First, OXTRs on DA VTA neurons will be silenced in male and female rats using a transgenic Cre rat and Cre-dependent knockdown of OXTRs to determine the effect of OXT-mediated DA firing rate. Behaviorally, OXT attenuates cocaine preference behaviors, and it is expected that silencing of OXTRs on VTA DA neurons will diminish this effect. Second, to further elucidate the specific mechanism through which OXT attenuates cocaine preference via VTA DA neurons, CB1Rs on VTA glutamatergic inputs will be silenced using a combination of transgenic Cre rat and shRNA silencing of CB1R in the absence of Cre expression. OXT is known to reduce neuronal excitation through production of endocannabinioids (eCB) that retrogradely reduce presynaptic input via CB1 receptors. Through this, the effect of glutamatergic CB1R silencing will be assessed on OXT-mediated VTA DA phasic neuronal firing. Behaviorally, this demonstrates that OXT-mediated reduction of VTA DA phasic firing underlies OXT-mediated attenuation of cocaine-associated preference. Overall, this project will utilize a novel combination of tools to investigate the specific neural mechanism through which OXT attenuates cocaine reward and offer insight into the use of OXT as a therapeutic target for cocaine-related disorders in males and females.